One of the most important factors in the survival of cancer is detection at an early stage. Clinical assays that detect the early events of cancer offer an opportunity to intervene and prevent cancer progression. With the development of gene profiling and proteomics there has been significant progress in the identification of molecular markers or “biomarkers” that can be used to diagnose and prognose specific cancers. For example, in the case of prostate cancer, the antigen PSA (for prostate specific antigen) can be detected in the blood and is indicative of the presence of prostate cancer. Thus, the blood of men at risk for prostate cancer can be quickly, easily, and safely screened for elevated PSA levels.
Even though there has been significant progress in the field of cancer detection, there still remains a need in the art for the identification of new biomarkers for a variety of cancers that can be easily used in clinical applications. For example, to date there are relatively few options available for the diagnosis of breast cancer using easily detectable biomarkers. Overexpression of EGFR, particularly coupled with down-regulation of the estrogen receptor, is a marker of poor prognosis in breast cancer patients. In addition, up-regulation of Cyr61 in breast cancer tumor tissue samples has been noted in U.S. patent application No. 20040086504, however, detection of Cyr61 involves invasive procedures and the use of urine for analysis of Cyr61 is not taught. Other markers of breast cancer include high levels of M2 pyruvate kinase (M2 PK) in blood (U.S. Pat. No. 6,358,683), high ZNF217 protein levels in blood (WO 98/02539), and differential expression of a newly identified protein in breast cancer, PDEBC, which is useful for diagnosis (U.S. patent application No. 20030124543). These biomarkers offer an alternative method of diagnosis, however, they are not widely used and many involve invasive procedures for detection. Furthermore, despite the use of a number of histochemical, genetic, and immunological markers, clinicians still have a difficult time predicting which tumors will metastasize to other organs.
The identification of biomarkers is particularly relevant to improving diagnosis, prognosis, and treatment of the disease. As such, there is need in the art to identify alternative biomarkers that can be quickly, easily, and safely detected. Such biomarkers may be used to diagnose, to stage, or to monitor the progression or treatment of a subject with cancer. Biomarkers can also be used to differentiate between organ confined and metastatic cancers.
Biomarkers that are involved in the “angiogenic switch” of tumors are particularly useful because tumor growth and metastasis are angiogenic dependent. When a tumor becomes angiogenic, the tumor expands progressively and can disseminate metastatic cells (Hanahan D, Folkman J., Cell 86:353-364, 1996; Smith-Mcune and Weidner N., Cancer Research, 54: 800-804). Thus, identification of biomarkers involved in the switch of a tumor to an angiogenic state will enable one to diagnose organ confined and metastatic cancer.